TY - JOUR
T1 - Cytochrome bd as survival factor in mycobacteria
AU - Lu, Ping
AU - Heineke, Marieke
AU - Koul, Anil
AU - Andries, Koen
AU - Cook, Gregory M.
AU - Lill, Holger
AU - van Spanning, Rob
AU - Bald, Dirk
PY - 2016/8
Y1 - 2016/8
N2 - Targeting respiration and ATP synthesis has received strong interest as a new strategy for combating drug-resistant Mycobacterium tuberculosis [1,2]. Mycobacteria employ a respiratory chain terminating with two branches. One of the branches includes a cytochrome bc1 complex and an aa3-type cytochrome c oxidase while the other branch terminates with a cytochrome bd-type quinol oxidase. We have shown that genetic inactivation of cytochrome bd, but not of cytochrome bc1, enhances the susceptibility of Mycobacterium smegmatis to hydrogen peroxide and antibiotic-induced stress [3]. The type-II NADH dehydrogenase effector clofazimine and the ATP synthase inhibitor bedaquiline were bacteriostatic against wild-type M. smegmatis, but strongly bactericidal against a cytochrome bd knock-out mutant [3,4]. These results identify cytochrome bd as a key survival factor in mycobacteria. The quinone-analog aurachin D inhibited mycobacterial cytochrome bd at sub-micromolar concentrations. Progress towards the characterization of cytochrome bd and its inhibitors will be discussed. Targeting the cytochrome bd respiratory branch appears to be a promising strategy that may enhance the bactericidal activity of existing tuberculosis drugs.
AB - Targeting respiration and ATP synthesis has received strong interest as a new strategy for combating drug-resistant Mycobacterium tuberculosis [1,2]. Mycobacteria employ a respiratory chain terminating with two branches. One of the branches includes a cytochrome bc1 complex and an aa3-type cytochrome c oxidase while the other branch terminates with a cytochrome bd-type quinol oxidase. We have shown that genetic inactivation of cytochrome bd, but not of cytochrome bc1, enhances the susceptibility of Mycobacterium smegmatis to hydrogen peroxide and antibiotic-induced stress [3]. The type-II NADH dehydrogenase effector clofazimine and the ATP synthase inhibitor bedaquiline were bacteriostatic against wild-type M. smegmatis, but strongly bactericidal against a cytochrome bd knock-out mutant [3,4]. These results identify cytochrome bd as a key survival factor in mycobacteria. The quinone-analog aurachin D inhibited mycobacterial cytochrome bd at sub-micromolar concentrations. Progress towards the characterization of cytochrome bd and its inhibitors will be discussed. Targeting the cytochrome bd respiratory branch appears to be a promising strategy that may enhance the bactericidal activity of existing tuberculosis drugs.
U2 - 10.1016/j.bbabio.2016.04.257
DO - 10.1016/j.bbabio.2016.04.257
M3 - Article
VL - 1857
SP - e120
JO - Biochimica et Biophysica Acta (BBA) - Bioenergetics
JF - Biochimica et Biophysica Acta (BBA) - Bioenergetics
SN - 0005-2728
ER -